Genetic Susceptibility Analysis In Primary Biliary Cirrhosis: Family-based Association Test

BackgroundPrimary biliary cirrhosis(PBC) is a chronic inflammatory autoimmune liver diease. Histopathologically, primary biliary cirrhosis is characterized by portal inflammation and immune-mediated destruction of the small intrahepatic bile ducts, gradually leading to cholestasis. Without treatment, PBC generally progresses to cirrhosis and eventually liver failure over a period of 10–20 years. With the improvement of diagnosis and therapy, with the greater recognition of PBC by people, the incidence of PBC is increasing year by year. The most of the patients are asymptomatic earlier, they have attained the advanced stage when at diagnosis.It is important to diagnose and treat patients timely at earlier stage in order to prevent disease progression and improve survival rate. However, the etiological factors contributing to disease development and the mechanism of PBC remain a mystery. A lot of previous epidemiological studies have showed that PBC is characterized by family aggregation.Epidemiological studies from every countries showed that a higher incidence of disease among first-degree relatives of patients at 1.0-7.1%, compared to ranges from 10 to 200 per million in the general population. The PBC concordance rate among monozygotic twins is as high as 63%. It is reported that 61% patients have a family history of immune disorder and 14% have a family history of autoimmune diseases (excluding PBC) [1]. All these data showing family aggregation of PBC indicated that genetic susceptibility play a crucial role in PBC. It is currently considered that PBC pathogenesis is the interplay of genetic susceptibility and environmental factors.As an autoimmune liver disease, PBC is thought to result from a combination of derangement of immune-regulation. We aimed to study the molecules in signaling transduction path including IL-12 which regulate the differentiation, proliferation and positive selection of Th1 cells. These molecules of interleukin-12 immunoregulatory signaling axis, including STAT4, IRF5, INF-γ, and so on, is relevant to the pathophysiology of primary biliary cirrhosis. Other molecules participating in proliferation and positive selection of T cells include CTLA-4, PTPN22 and MHC.ObjectiveOur study was to investigate Genetic Susceptibility Analysis in Primary Biliary Cirrhosis using Family-based Association Test. Our study mainly focuses on the genes related to immune response. We aimed to find out the genes highly correlation with PBC, in order to understand the mechanisms of PBC.MethodsThis study described 94 patients and 206 normal cases of FDRs in 80 PBC families in China. Establish the database of blood serum and DNA of these samples. Autoantibodies were detected in each serum sample by indirect immunofluorescence and immunoblotting. We checked out loci in genes in each DNA sample using SNP array.ResultsThese subjects comprised 94 patients, 106 FDRs of these patients. Ten of eighty families had at least two PBC patients. The incidence of familial PBC accounted for 12.5% in our study, obviously higher than the incidence of PBC in the general population.14 in all the FDRs were diagnosed of abnormal results autoantibodies tests during the study. All had ANA positive and AMA positive by immunofluorescence. ANA spectrum revealed that AMA-M2 type positive of +～++++. They were initially sceptical to be PBC patients by these positive antibodies. Then we made a definite diagnosis by a series of examination.We analyzed genetic SNP susceptibility in PBC using family-based association test. We studied three loci (rs3790567, rs3790565, rs6679356) in IL-12RB2 and three loci (rs6748358, rs16833239, rs7574865) in STAT4 using SNP array. We found that the minor A allele of rs3790567 in IL-12RB2 and the minor T allele of rs7574865 in STAT4 had highly relationship with PBC genetic susceptibility.ConclusionThe incidence of familial PBC in China is about 12.5% showed clustering of disease within PBC families. Moreover, our experiment indicated that rs3790567 in IL-12RB2 and rs6748358 in STAT4 had highly relationship with PBC. These data point to the possibility that modulation of signaling by interleukin-12 and its receptor may be beneficial in our understanding the mechanism of primary biliary cirrhosis and guidance in treatment of PBC patients.